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Potent vasorelaxant activity of the TMEM16A inhibitor T16A inh ‐A01
Author(s) -
Davis Alison J,
Shi Jian,
Pritchard Harry AT,
Chadha Preet S,
Leblanc Normand,
Vasilikostas Georgios,
Yao Zhen,
Verkman AS,
Albert Anthony P,
Greenwood Iain A
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02199.x
Subject(s) - methoxamine , chemistry , aorta , thoracic aorta , vascular smooth muscle , chloride channel , anatomy , potassium channel , contraction (grammar) , medicine , endocrinology , biophysics , biochemistry , biology , smooth muscle , agonist , receptor
Background and Purpose T16A inh ‐A01 is a recently identified inhibitor of the calcium‐activated chloride channel TMEM16A . The aim of this study was to test the efficacy of T16A inh ‐A01 for inhibition of calcium‐activated chloride channels in vascular smooth muscle and consequent effects on vascular tone. Experimental Approach Single channel and whole cell patch clamp was performed on single smooth muscle cells from rabbit pulmonary artery and mouse thoracic aorta. Isometric tension studies were performed on mouse thoracic aorta and mesenteric artery as well as human abdominal visceral adipose artery. Key Results In rabbit pulmonary artery myocytes T16A inh ‐A01 (1–30 μM ) inhibited single calcium ( Ca 2+ )‐activated chloride ( Cl − ) channels and whole cell currents activated by 500 nM free Ca 2+ . Similar effects were observed for single Ca 2+ ‐activated Cl − channels in mouse thoracic aorta, and in both cell types, channel activity was abolished by two antisera raised against TMEM16A but not by a bestrophin antibody. The TMEM16A potentiator, F act (10 μM ), increased single channel and whole cell Ca 2+ ‐activated Cl − currents in rabbit pulmonary arteries. In isometric tension studies, T16A inh ‐A01 relaxed mouse thoracic aorta pre‐contracted with methoxamine with an IC 50 of 1.6 μM and suppressed the methoxamine concentration–effect curve. T16A inh ‐A01 did not affect the maximal contraction produced by 60 mM KCl and the relaxant effect of 10 μM T16A inh ‐A01 was not altered by incubation of mouse thoracic aorta in a cocktail of potassium ( K + ) channel blockers. T16A inh ‐A01 (10 μM ) also relaxed human visceral adipose arteries by 88 ± 3%. Conclusions and Implications T16A inh ‐A01 blocks calcium‐activated chloride channels in vascular smooth muscle cells and relaxes murine and human blood vessels.